Download Safety and efficacy of PTK 0796 (Omadacycline) as treatment of

P 694
Safety and efficacy of PTK 0796 (Omadacycline) as treatment of
complicated skin and soft tissue infection (cSSTI)
75 Kneeland Street
Boston, MA 02111
Gary J. Noel*, Michael Draper, Howard Hait, S. Ken Tanaka
(Boston, Massachusetts US)
617.275.0040
[email protected]
ABSTRACT
RESULTS
RESULTS (continued)
Background Having completed phase 1 and 2 clinical programs,
PTK 0796, an aminomethylcycline, broad-spectrum antibacterial
agent active against all the leading causes of cSSTI including
methicillin-resistant Staphylococcus aureus (MRSA), has begun
assessment in phase 3 trials.
Methods A randomized (1:1), controlled, evaluator-blind, stratified
by infection type, trial comparing PTK 0796 (100mg iv; 300mg po
QD) to linezolid (LZD; 600mg iv/po BID) was designed to establish
non-inferiority
non
inferiority between treatment arms regarding efficacy based on
clinical assessment immediately after (EOT), and 10-17 days after
(TOC) completing therapy in the intent-to-treat (ITT) and clinically
evaluable (CE) populations. Subjects were given iv therapy initially
with an option to transition to oral formulations of either PTK 0796
or LZD. Moxifloxacin (400 mg QD) was added to LZD treatment if
infection due to Gram-negative bacteria was suspected.
Results The trial was administratively stopped to address
alignment with a new FDA guidance on ABSSSI, after 143 of the
planned 790 subjects were enrolled. Subjects enrolled at 6 sites
with 140 and 127 qualifying for the ITT and CE populations,
respectively. A total of 44 (65%) PTK 0796 and 48 (67%) LZD
subjects had cellulitis and 14 (21%) PTK 0796 subjects and 14
(19%) LZD subjects (19%) had wound infections. The mean and
median duration of therapy were 10.1 and 10.0 days for PTK 0796
and 9.9 and 9.5 days for LZD subjects. MRSA was the most
frequently isolated pathogen and success in the CE population
occurred in 96.2% (25/26) with PTK 0796 and 93.5% (29/31) with
LZD ttreatment.
t
t There
Th
were comparable
bl numbers
b
off treatment
t t
t
emergent adverse events (56;82.4% in PTK 0796 and 58;80.6% in
LZD) and study-drug related adverse events (41;60.3% in PTK
0796 and 41;56.9% in LZD) across treatment arms. The most
common adverse events reported involved the gastrointestinal
system and the most common of these was nausea, reported by 18
PTK 0796 and 19 LZD treated subjects.
Conclusions Results of this phase 3 trial experience are consistent
with those of the phase 2 clinical program that also involved
patients with cSSTI and showed comparable efficacy and overall
safety/tolerability between PTK 0796 and LZD. Although stopped
before meeting planned enrolment goals, results in the CE
population met the protocol-defined criteria of a 10% margin to
conclude non-inferiority between treatments.
Patients were enrolled in this study between April 2009 and March 2010 in 6 US
sites. The trial was stopped after 17% (140/790) of the planned sample size was
enrolled. The following characteristics of patients enrolled were noted:
•
The mean age of patients randomized into PTK 0796 was 5.5 years older
than linezolid-treated patients (~70% of linezolid-treated patients were < 44
years of age compared to 56% in the PTK 0796-treatment arm).
•
Approximately 20% of patients enrolled were Hep C seropositive (10-fold
higher incidence than estimated in the general popoulation).
More than 1/3 (35.3%) of PTK 0796 treated patients had infections involving
•
the lower extremity. This compared to <25% (23.6%) in the linezolid
treatment arm.
POST-HOC ANALYSIS: reduction in lesion size
This study was initiated well before the issuance of the August 2010
FDA guidance for study of Acute Bacterial Skin and Skin Structure
Infections (ABSSSI) (2) which identified changes in lesion size as
central to conclusions about antibiotic effect. However, patients in
the trial were scheduled to have the maximal lesion dimension
recorded at scheduled study visits (end of IV therapy, EOT, TOC). In
some instances, the end of iv therapy occurred during the first 72
py All p
patients had the maximal lesion dimension
hours of therapy.
measured at baseline. Given the recent interest on assessing
progress of lesion size in patients with ABSSSI (lesions >75 cm2 ), a
post-hoc analysis was done that compared across treatment arms
on the changes in maximal lesion dimension . This analysis was
focused on patient’s whose lesion had a maximal dimension of
>10cm to approximate the 75 cm2 criteria that is evolving as a
definition of ABSSSI.
INTRODUCTION
PTK 0796 is the first antibiotic of a new class of compounds, the
aminomethylcyclines,
i
th l li
which
hi h are semi-synthetic
i
th ti compounds
d related
l t d
to the tetracyclines. In addition to activity against tetracyclinesusceptible organisms, PTK 0796 is active both in vitro and in
animals against Gram-positive pathogens expressing tetracycline
resistance. The drug is also active in the presence of resistance to
other antibiotics including methicillin, vancomycin, erythromycin,
and ciprofloxacin. Thus, PTK 0796 represents a potentially
important option in the treatment of resistant pathogens that are
becoming an increasing problem.
The targeted indications for PTK 0796 encompass a range of
serious acute bacterial infections, either prompting or occurring
during hospitalization. Currently, these include complicated skin and
skin structure infection and community-acquired pneumonia.
The study was designed to compare the safety and efficacy of
PTK 0796 with linezolid (Zyvox®) in the treatment of adults with
complicated skin and skin structure infections (cSSSI).
STUDY DESIGN
This was a randomized (1:1), stratified, controlled, evaluatorblinded Phase 3 study comparing PTK 0796 and linezolid (Zyvox™)
for the treatment of adults with complicated skin and skin structure
infections. All patients had four scheduled evaluations: at
Enrollment (Baseline); at End of IV Treatment; at End of Treatment;
and at 10 to 17 days after the last dose of treatment (Test of Cure
Evaluation).
Patients were stratified at study entry by type of infection (i.e.,
wound infection, cellulitis, major abscess). Enrolment of patients
with major abscess was limited to 20% Patients were initially
treated with study drug IV and then switched to oral therapy at the
discretion of the Investigator. The expected duration of IV treatment
was 4-7 days; the expected total duration of treatment (IV and oral)
was up to 14 days. The study was double-blinded during the IV
treatment phase and Evaluator-blinded during the oral treatment
phase. The primary hypothesis was evaluated by analysis of
the clinical success rates in the intent-to-treat (ITT) and
clinically evaluable (CE or per protocol) . The two analyses
were treated as co-primary. The 95% confidence intervals were to
be calculated for the difference in success rates between the two
treatment groups for each population. If the lower limit of the 95%
confidence interval for [PTK 0796 – linezolid] was greater than or
equal to –10% for both endpoints, then the hypothesis that PTK
0796 is non-inferior to linezolid would be supported. Should the
lower limit of the 95% confidence interval exceed 0% then the
superiority of PTK 0796 over linezolid would be supported. With 790
subjects randomized 1:1 with required distribution among infection
types, there would be 395 subjects in each treatment group for the
total ITT population and at least 316 subjects with cellulitis and
wound infection only. A comparator success rate of 75% was
assumed in the ITT population (where non-evaluable subjects were
failures) and 85% in the CE population. With an evaluability rate of
85% and a two-sided significance level of 0.05, the study would
have ~90% power for each of the co-primary endpoints.
The study was designed to align with the 1998 FDA guidance on
developing antimicrobial drugs for the treatment of complicated skin
and skin structure infections (1). After the study was initiated, FDA
modified its guidance for the conduct of studies for this indication.
This modification included changes in criteria defining the disease
indication (cSSSI to acute bacterial skin and skin structure
infections (ABSSSI)) as well as focus of the primary efficacy
endpoint to an early response assessment rather than a test of cure
assessment. With these major modifications, the trial design did not
align with the FDA’s guidance for trials aimed at supporting the
approval of an antibiotic for treatment of ABSSSI. As a result, the
trial was administratively terminated after having enrolled 143 of the
planned 790 subjects.
Table 1.
Demographics and baseline characteristics
Mean age in years + SD
Age category: >18 to <44; n (%)
>44 to <64; n (%)
>64; n (%)
Sex
Male
Female
Race
Caucasian
Black
Hepatitis C seropositive
n (%)
Type of qualifying infection
Wound infection
Cellulitis
Major abscess
Primary location of qualifying infection
Head and neck
Chest/Thorax (below neck to umbilicus)
Abdomen/Buttocks/Upper Thigh (umbilicus
to mid-thigh)
Right upper extremity (shoulder to fingertips)
Left upper extremity (shoulder to fingertips)
Right lower extremity (below mid-thigh to toes)
Left lower extremity (below mid-thigh to toes)
Primary cause of infection
None apparent
Trauma
Surgery
PTK 0796
N=68
41.7 + 14.61
38 ( 55.9 )
26 ( 38.2 )
4 ( 5.9 )
Linezolid
N=72
36.2 + 12.53
51 ( 70.8 )
20 ( 27.8 )
1 ( 1.4 )
42
26
51
21
56
7
61
7
16 ( 23.5 )
14 ( 19.4 )
14 ( 20.6)
44 ( 64.7)
10 ( 14.7)
14 ( 19.4 )
48 ( 66.7 )
10 ( 13.9 )
6 ( 8.8 )
4 ( 5.9 )
17 ( 25.0 )
5 ( 6.9 )
4 ( 5.6 )
15 ( 20.8 )
10 ( 14.7 )
7 ( 10.3 )
13 ( 19.1 )
11 ( 16.2 )
16 ( 22.2 )
15 ( 20.8 )
6 ( 8.3 )
11 ( 15.3 )
33 ( 48.5 )
11 ( 16.2 )
1 ( 1.5 )
41 ( 56.9 )
9 ( 12.5 )
1 ( 1.4 )
EFFICACY ANALYSES
Clinical success in both the ITT and CE analysis populations were comparable
across treatment arms when measured at either the EOT or TOC evaluation.
Table 2. Clinical Response in the ITT population at EOT and TOC
PTK 0796 Linezolid
N=68
N=72
n (%)
n (%)
Visit
Clinical outcome
End of treatment (EOT)
Clinical success 61 ( 89.7 )
Not Clinical Success (failure + nonevaluable) 7 ( 10.3 )
Clinical failure (failure only) 1 ( 1.5 )
Test of cure (TOC)
Clinical success 58 ( 85.3 )
Clinical failure (failure + non-evaluable) 10 ( 14.7 )
Clinical failure (failure only) 2 ( 2.9 )
66 ( 91.7 ) -2.0 ( -12.4, 8.5 )
6 ( 8.3 )
3 ( 4.2 )
Success at End of treatment
All cSSSI patients
Wound
Cellulitis
Major Abscess
Success at Test of cure
All cSSSI patients
Wound
Cellulitis
Major Abscess
PTK 0796 Linezolid
Difference
(95% CI)
PTK 0796
Success /
Total (%)
Linezolid
Success /
Total (%)
59/60 (98.3)
13/13 (100)
38/39 (97.4)
8/8 (100)
64/67 (95.5)
12/13 (92.3)
44/45 (97.8)
8/9 (88.9)
2.8 (-12.4,
( 12.4, 8.5)
58/60 (96.7)
13/13 (100)
38/39 (97.4)
7/8 (89.5)
64/67(95.5)
12/13 (92.3)
44/45 (97.8)
8/9 (88.9)
1.1 (-6.5, 8.8)
Clinical success in patients in whom an infecting pathogen was identified was
comparable across treatment arms. MRSA was the frequently isolated pathogen.
Among patents with MRSA infections, successful clinical response was achieved
in 96.2% (25/26) patients treated with PTK 0796 and in 93.5% (29/31) patients
treated with linezolid.
Table 4. Clinical Response in the Microbiologically Evaluable
Population
All pathogens
Staphylococcus aureus methicillin susceptible
Staphylococcus aureus methicillin resistant
PTK 0796
Eradicated /
Total (%)
47/49 (95.9%)
Linezolid
Eradicated /
Total (%)
51/52 (98.1%)
17/18 (94.4%)
13/13 (100%)
25/26 (96.2%)
29/31 (93.5%)
N
62
Linezolid
Mean (SE)
20.75 (1.3)
N
63
Mean (SE)
22.80 (1.4)
Percent Reduction from Enrollment
EOIV: Subjects
12
-62.3% (4.7%)
12
-56.8% (6.3%)
Receiving 24-72
Hours of IV
EOIV
59
-60.4% (2.7%)
59
-62.5% (2.8%)
•
EOT
60
-81.3% (2.8%)
61
-86.3% (1.9%)
TOC
60
-92.3% (1.7%)
61
-92.5% (1.5%)
Most patients enrolled (62/68, 91.2% PTK 0796-treated and
63/72 87.5% of linezolid-treated) had lesions with a maximal
dimension that was >10cm.
Percent reduction in lesion size was comparable across treatment
arms
For the subset of patients who had measurements taken 24-72
hrs after starting therapy, the mean percent reduction was 62.3%
in PTK 0796-treated and 56.8% in linezolid-treated patients.
•
•
PHARMACOKINETIC ANALYSES
Plasma concentrations of PTK 0796 were
ere comparable to those
measured in healthy volunteers and phase 2 patients. Plasma
concentrations after 300mg oral dosing were comparable to that
achieved with 100mg i.v dosing.
Table 6. Omadacycline exposure in cSSTI patients
Infusion
1
Hours (Nominal)
Post Start of Infusion 1
1
3
6
24 (1 Hr Prior to Inf 3)
72 (1 Hr Prior to Inf 7)
3
7
1-3 Hours Following Oral Administration
Plasma Concentration
ng/mL
N
Mean Std Dev
46
896.0
1183.4
41
403.2
118.7
32
293.8
103.8
44
136.4
116.1
36
234.9
260.4
27
399.8
243.3
AUC0-24 hr·ng/ml
AUC0-24 for
f Infusion
I f i 1
(Using Actual Sampling Times for
Trapezoidal Rule)*
24
6096.6
3463.2
SAFETY ANALYSES
The overall incidence of adverse events was similar in both
treatment groups. The only notable difference favoring comparator
was in headache. No subject discontinued study drug due to
headache and 12/16 reports of headache in PTK 0796 treated
subjects were mild. This observed frequency of headache in PTK
0796 treated subjects is not consistent with that seen in the Phase 2
(CSSI-0702) trial where headache was reported less frequently
overall, and occurred more frequently in linezolid than in PTK 0796treated subjects (6.3%; 7/111 v 8.3% 9/109). The 1 death occurred in
a patient with metastatic lung cancer, 14 days after TOC. No SAE
reported was considered to be study drug related.
Table 7.
Adverse events in PTK 0796 and Linezolid
treated patients
PTK 0796
Linezolid
N=68; n (%) N=72; n (%)
Treatment-emergent AE (TEAE)
56 ( 82.4)
58 ( 80.6)
Study drug related TEAE
41 ( 60.3)
41 ( 56.9)
AEs leading to study drug discontinuation
2 ( 2.9)
0
Serious TEAE
3 ( 4.4)
1 ( 1.4)
Death
1 ( 1.5)
0
TEAEs occurring in >10% of patients in either treatment group
Nausea 18 ( 26.5)
19 ( 26.4)
Vomiting
6 ( 8.8)
11 ( 15.3)
Diarrhea
3 ( 4.4)
13 ( 18.1)
Headache 16 ( 23.5)
5 ( 6.9)
Dizziness 7 ( 10.3)
6 ( 8.3)
CONCLUSIONS
•
PTK 0796 - Linezolid
Difference (95% CI)
-2.2 (-9.9, 5.6)
PTK 0796
Time Point
64 ( 88.9 ) -3.6 ( -15.5, 8.3 )
8 ( 11.1 )
3 ( 4.2 )
Table 3. Clinical Response in the CE (per-protocol) population at
EOT and TOC
Mean (SE) Percent Change in Maximal Lesion
Dimension Among ITT Subjects With
Baseline Maximal Lesion Dimension of ≥ 10cm
Enrollment (Maximal
Lesion Dim in cm)
PTK 0796 Linezolid
Difference
(95% CI)
In addition to observing comparable clinical success rates in the overall CE and
ITT analysis populations, success rates for patients characterized by cSSSI
subtype (wound, cellulitis, major abscess) were also comparable across
treatment arms.
Visit
Clinical outcome
Table 5.
•
•
(1)
(2)
Although stopped well short of the planned enrollment,
enrollment the
results in this phase 3 trial are consistent with those reported
in the phase 2 cSSSI trial and support the conclusion that
PTK 0796 (omadacycline) is not inferior to linezolid as a
treatment of patients with serious infections involving the skin
and adjacent structures.
Intravenous and oral formulations of PTK 0796 were well
tolerated
This experience supports the continued development of
PTK 0796 for the treatment of patients with serious infectious
diseases.
REFERENCES
US FDA. Guidance for industry: Uncomplicated and complicated skin and skin structure infections—developing antimicrobial
drugs for treatment. 1998 Jul.
US FDA Center for Drug Evaluation and Research (CDER) “Guidance for Industry: ABSSI: Developing Drugs for Treatment”
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071185.pdf
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